1-Imidazolylalkylene-piperidines

ABSTRACT

A group of imidazolyl compounds useful in the treatment of disorders and diseases of the cardiovascular system and/or in the treatment of superficial and deep allergic phenomena is described. These compounds or piperidine compounds linked by the nitrogen atom to an imidazolyl group through the intermediary of a lower-alkylene radical. The piperidine ring is further substituted by an acylamino residue.

United States Patent [191 Cavalla et al.

[451 Sept. 23, 1975 l-(IMIDAZQLYLALKYLENE)-PIPERIDINES Inventors: John Frederick Cavalla, lsleworth;

John Leheup Archibald, Windsor, both of England Assignee: John Wyeth 8!, Brother Limited,

Maidenhead, England Filed: Nov. 15, 1974 Appl. No.: 524,027

Related US. Application Data Continuation-in-part of Ser. No. 323,684, Jan. 15,

1973, which is a continuation-in-part of Ser. No. 175,345, Aug. 26, 1971, abandoned.

Foreign Application Priority Data V Sept. 3, 1970 United Kingdom 42090/70 U.S. Cl 260/293.7; 260/293.58; 260/295 F; 260/295 AM; 260/295 0; 260/293.77; 2'60/309; 424/267 Int. Cl. C07D 211/58 Field of Search 260/293.7, 293.58

[56] References Cited UNITED STATES PATENTS 3,821,234 6/1974 Koppe et al. 260/293.7

OTHER PUBLICATIONS Chemical Abstracts 77: 34, 3552 (1972), Archibald et al.

Chemical Abstracts 79: 136, 989t (1973), Archibald.

Primary ExaminerSherman D. Winters [57] ABSTRACT 2 Claims, No Drawings III(a) Pharmaceutical Compositions" and now abandoned. The invention provides an imidazolyl compound of the general formula:

in which W represents imidazolyl, A represents a lower alkylene radical of l to 4 carbon atoms, R represents a radical selected from phenyl and phenyl substituted by halogen, lower alkoxy, lower alkyl, or lower alkylenedioxy and the pharmaceutically"acceptable acid addition salts thereof.

It is to be understood that the term alkylene used herein includes both straight and branched chain radieals.

The eompound of formula (I) and the pharmaceutically acceptable acid addition salts thereof exhibit pharmacological activity for example one or more of the following activities: action on the cardiovascular system (such as hypotensive and/or anti-hypertensive and/or peripheral vasodilation and/or anti-anginal and- /or anti-arrhythmic activity), anti-histamine activity such as activity against superficial and deep allergic phenomena for example Urticaria, Pruritus, Allergic Rhinitis, Anaphylactie shock and. Asthma when tested on warm blooded animals.

In addition to having useful pharmaceutical properties as mentioned above the novel compounds of the invention are intermediates for the preparation of other compounds of formula I. The other compounds of the invention are also intermediates for the preparation of pharmacologically active compounds.

The imidazolyl radical W may for example be a 4- imidazolyl group. The phenyl radical R may be substituted by one or more groups, which may be the same -or different selected from halogen (for example fluorine, chlorine or bromine), lower alkyl (for example methyl, ethyl, propyl, or n, s and t-butyl), lower alkoxy (for example methoxy, ethoxy, propoxy or butoxy), lower alkylenedioxy (for example methylenedioxy).

Examples of A are methylene, ethylene, propylene, methylenethylene and butylene. Examples of acid addition salts are those formed from inorganic and organic acids in particular pharmaceutically acceptable acid addition salts such as the sulphate, hydrochloride, hydrobromide, hydro-iodide, nitrate, phosphate, sulphonate (such as the methane-sulphonate and p-toluenesulphonate), acetate, maleate, fumarate, tartrate and formate.

The compounds of general formula (I) can be pre pared in a number of ways by building up the molecule from suitable startingmaterials in known manner. Such processes applied to the preparation of the novel compounds of formula (I) are included in the scope of the invention.

One method of preparation of compounds of general 5 formula (I) comprises reacting a compound of the general formula:

NHCUR NHCUR NHCUR l'iN 0 I H N "III (In) 111(0) with an alkylating or acylating agent of the general formula.

[W] AY where R, W and A have the meanings already defined and Y is a halogen atom or an equivalent replaceable atom or radical, for example an organic sulphonyl radical such as tosyl radical. If a compound of formula Illa or IIIb is used the product containing a pyridinium or tetrahydropyridine ring may be reduced to the desired compound of formula I as described below.

The compounds of general formula (IV), are known compounds or can be made following the methods known for preparing compounds of these types. The starting materials of general formulae IIl(a), III(b) and III(c) can generally be made by acylating a corresponding amino compound of the general formula:

(VIII) N NHCUR with a benzyl halide, for example benzyl chloride to give the quaternary salt, reducing with an alkali metal borohydride to. give the corresponding N-benzyl-tetrahydro-pyridine which is further subjected to concomitant de-benzylation and reduction of the 3,4-double bond by catalytic hydrogenation, or (iii) catalytic hydrogenation of compound (IX) in the presence of acetic anhydride to give:

GIBBS-N NHCUR and then selectively hydrolysing the acetyl group.

The compounds of general formula (I) may be prepared by starting with a compound of formula:

R. CO NH N-A-T wherein T is a known precursor group of W and reacting with another molecule of the type known in the literature for the formation of W. Reference may be made in this connection to standard textbooks of Organic Chemistry such as: Organic Chemistry by Paul Karrer (Elsevier Publishing Company, Inc., 1950); Organic Chemistry by Fieser and Fieser (Reinhold Publishing Corporation, 1956); Chemistry of Carbon Compounds by Rodd (Elsevier), Amsterdam, 1951-1969); Heterocyclic Compounds edited by Elderfield (John Wiley and Sons, Inc., 1950-1968); and Chemistry of the Heterocyclic Compounds edited by Weissberger (Interscience, 1954). As examples of T may be mentioned CO.CI-I .OH which when treated with a mixture of formaldehyde and ammonia gives [W]. The compounds of formula XI may be made following methods known in the art for the preparation of similar compounds. i

A further aspect of the invention is the provision of a further process for the preparation of compounds of general formula (I) in which W and R have the meanings defined in connection with formula (I). This consists of reacting a compound of the general formula:

[W]A OH (XVI) (in which W, and A have the meanings defined immediately above) with a compound of formula lII(c).

The reaction is preferably carried out in the presence of a catalyst, for example Raney Nickel. An organic solvent, which is inert under the reaction conditions, is usually used for example xylene, toluene or benzene. Preferably the reaction is carried out by heating the re actants under reflux in a water-immiscible organic solvent, for example xylene, and removing the water formed during the reaction by azeotropic distillation. If necessary, reactive substituent groups can be blocked during a reaction and released later.

The reactions outlined above usually are carried out in a solvent which is inert under the reaction conditions. The most suitable solvent system is chosen and varies depending on the particular reactants being employed. If necessary heating the reactants in solution under reflux can be carried out, and if necessary heating under high pressures may also be used.

Once a compound of general formula (I) has been prepared, then if necessary one or more substituents in the molecule may be converted to another substituent each within its own meanings specified in connection with formula (I). If a compound is produced'from a starting compound of III( a) and therefore contains the pyridinium ring system this may be selectively reduced to the piperidine ring. For example reduction with an alkali metal borohydride under conditions such as refluxing isopropanol gives rise to the piperidine ring'system. Similarly, if a compound of formula (I) is prepared from a compound of formula IlI(b) an intermediate containing the tetrahydropyridine ring system is produced which may then be reduced to the piperidine ring system using a borohydride.

When a compound of formula (I) is produced wherein the radical W has one or more methoxy substituents, demethylation to the corresponding hydroxyl Furthermore, if the radical W has a nitro substituent this may be reduced in known manner to the corresponding amino compound which in turn may be further acylated or alkylated.

Compounds of formula I in which A is a branched chain alkylene radical possess an asymmetric carbon atom and are therefore capable of existing in optically active stereo isomeric forms. The optical isomers may be separated by standard resolution procedures. For instance compounds of formula I contain a basic nitrogen atom and may generally be resolved by treatment with a suitable optically active acid. Optically active acids are described in the literature and suitable ones for the resolution of any particular compound are chosen by experiment.

If necessary, in any of the reactions hereinbefore described, reactive substituent groups may be blocked during a reaction and released at a later stage. As already indicated the novel compounds provided by the invention contain basic nitrogen atoms and thus can form acid addition salts with acids (particularly pharmaceutically acceptable acids) or quaternary ammonium salts, for example with alkyl halides or aralkyl halides (particularly methyl iodide or benzyl chloride or bromide). The acid addition salts may either be formed in situ during the hereinbefore described processes and isolated therefrom or a free base may be treated with the appropriate acid in the presence of a suitable solvent and then the salt isolated. The quaternary salts may be prepared by treating the free base with the appropriate halide in the presence or absence of a solvent.

'The compounds of the invention may be formulated into pharmaceutical compositions as active ingredient containing a compound of formula (I) as hereinbefore defined, whichmay be micronised. In addition to the active ingredient, said compositions also contain a nontoxic carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet-disintegrating agents; it'can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredients is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, trag'acanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The

term composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carrier, which is thus inassociation with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterileor'ganic solvent or a mixture of Compound y be brought about in known mannerboth. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dis solved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form. In such form, the composition is subdivided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 5 mg. or less to 500 or more, according to the particular need and the activ ity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The following non-limiting examples illustrate the invention:

EXAMPLE 1 I 2-( 4-Imidazolyl )ethyl -4-benzamidopiperidine a. 4-Benzamidopiperidine (2.4 g.) in ethanol ml.) was added to hydroxymethylvinyl ketone (2.0 g.). An

exothermic reaction occurred and crystallisation occurred on cooling to give 2-(4- benzamidopiperidine)ethyl hydroxymethyl ketone,

m.p. 154 l55C. (Found: C, 65.9; H, 7.7; N, 9.5; C16H22N2O3 requires C, H, N,

b. the foregoing product (3.0 g.) in ethanol (10 ml.) was added to a mixture of cupric acetate (5 g.) 0.880 ammonia (40 ml.) and 40% aqueous formaldehyde (3 ml.). The reaction mixture was heated on a steam bath for 1 hour. The copper salt was collected, suspended in hot water and brought to pI-I3. Hydrogen sulphide was passed in until there was no further precipitation then taining anhydrous K CO for 24 hr. The mixture is filtered and evaporated to afford the title compound.

7 EXAMPLE 3 1 -[4-(4-Imidazolyl)butyl]-4-( 3-methoxy)benzamidopiperidine 4-(3-Methoxy)benzamidopiperidine and 4-(4- chlorobutyl)-imidazole are condensed in the manner of Example 2 to give the title compound.

EXAMPLE 4 -[4-(4-Imidazolyl)butyl]-4-( 4- y nzamidopiperidine 4-( 4-Methyl )benzamidopiperidine and 4-( 4- chlorobutyl) imidazole are condensed in the manner of Example to give-the title compound.

EXAMPLE 5 l- 4-( 4-Imidazolyl )butyl -4-( 3 ,4-methylenedioxybenzamidopiperidine 4-( 3 ,4-Methylenedioxybenzamido )piperidine and 4-(4-chlorobutyl)imidazole are condensed in the manner of Example 2 to give the title compound.

EXAMPLE 6 4-( 4-Chlorobutyl )imidazole Imidazol-4-yl-4-butanol hydrochloride is refluxed with purified thionyl chloride for 3 hrs. The mixture is evaporated and the product purified to give the title compound hydrochloride.

Tests for action on the cardiovascular system were conducted according to one of the following procedures:

Hypotensive and/or Anti-Hypertensive activity Method 1 (Rat) Method 1 (Cat) Cats were anaesthetised with pentobarbitone sodium (30'mg/kg) and the cephalic vein, femoral and carotid arteries and trachea were cannulated. The carotid cannula was introduced into the left ventricle and the femoral cannula into the aorta. Blood pressure and heart rate were recorded from the aortic cannula and left ventricular pressure from the carotid cannula. The test compounds were administered intravenously (O. l25 .6

mg/kg).

Method 2 (hypertensive rats) Male or female rats are rendered hypertensive by applying a figure of 8 ligature around one kidney and contralateral nephrectomy. Blood pressure stabilises at a hypertensive level after 6 weeks. Systolic pressure is measured indirectly using a Decker Caudal Plethysmograph. A control group of rats is run with each group treated with drug. Each group usually consists of six rats. Drugs are usually administered by the IP or oral routes. Pressures are read prior to drug administration and at two and 24 hours thereafter.

a-Adrenoceptor Antagonism Activity Carried out on the guinea pig aortic strip [Furchgott and Bhadrakom (1953) J. Pharmac. exp. Ther. 108, 129-143] by the method of Alps et al [Br. J. Pharmac. 1972 44, 52-62].

Antihistamine activity was determined by the method of Alps et al [Br. J. Pharmacol. 1972, 44, 52-62].

Activity in either method 1 (rats or cats) or method 2 was considered to indicate hypotensive activity.

We claim:

1. An imidazolyl compound of the formula: 

1. AN IMIDAZOLYL COMPOUND OF THE FORMULA:
 2. A compound as claimed in claim 1 which is 1-(2-(4-imidazolyl)ethyl)-4-benzamidopiperidine or a pharmaceutically acceptable acid addition salt thereof. 